Systematic Review and Meta-Analysis: Early Treatment Responses of Selective Serotonin Reuptake Inhibitors and Clomipramine in Pediatric Obsessive-Compulsive Disorder  Anjali L. Varigonda, MD, Ewgeni Jakubovski, BA, Michael H. Bloch, MD, MS  Journal of the American Academy of Child & Adolescent Psychiatry  Volume 55, Issue 10, Pages 851-859.e2 (October 2016) DOI: 10.1016/j.jaac.2016.07.768 Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure 1 Selection of studies. Note: OCD = obsessive-compulsive disorder; RCT = randomized controlled trial; SSRI = selective serotonin reuptake inhibitor. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure 2 Selective serotonin reuptake inhibitor (SSRI) response in obsessive-compulsive disorder (OCD). Note: Differences in Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) ratings across time between patients treated with SSRIs and placebo. A) Weighted mean difference in CY-BOCS between SSRIs and placebo at time points. Error bars represent standard error. B) Best-fit model (logarithmically decreasing treatment response) for the weighted mean difference between groups. Dotted lines represent 95% CIs. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure 3 Clomipramine response in obsessive-compulsive disorder (OCD). Note: Differences in Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) ratings across time between patients treated with clomipramine and placebo. A) Weighted mean difference in CY-BOCS between clomipramine and placebo at time points. Error bars represent standard error. B) Best-fit model (logarithmically decreasing treatment response) for the weighted mean difference between groups. Dotted lines represent 95% CIs. These figures are based on data from 2 studies involving 76 participants. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure 4 Comparison of clomipramine and selective serotonin reuptake inhibitor (SSRI) response in obsessive-compulsive disorder (OCD). Note: A) Comparison of weighted mean difference in Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) of clomipramine and SSRIs when compared to placebo at time points. Error bars represent standard error. Clomipramine response is depicted with a solid line. SSRI response is depicted with a dotted line. B) Best-fit model (logarithmically decreasing treatment response) for the weighted mean difference between SSRIs and clomipramine compared to placebo. Clomipramine was associated with a significantly greater treatment effect than SSRIs. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure S1 Dose effect of selective serotonin reuptake inhibitor (SSRI) response in pediatric obsessive-compulsive disorder (OCD). Note: Each line represents separate isoquants in fluoxetine-equivalent SSRI doses. Meta-analysis demonstrated no effect of maximum SSRI dosing on therapeutic response in pediatric OCD. In the best fit model, there was neither a significant effect of time nor of the interaction of dose with time (log[week+]=-0.40 [95%CI: -3.48-2.67], p=.79; interaction=0.005 [95%CI: -0.007-0.017], p=.38). CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Disorder Scale. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure S2 Effect of publication year and recruitment year. Note: Figure S2A depicts the association between publication year and measured efficacy of selective serotonin reuptake inhibitor (SSRI) medications. Later publication year was associated with significantly decreasing treatment effect of SSRI compared to placebo. There was a significant effect of time and interaction between time and publication year in the best fit model (interaction=-0.22 [95% CI: -0.41 to -0.03]; p=.02; log[week+1]=443 [95% CI: 64.16-823.78] p=.02). Figure S2B depicts the relationship between trial start date and measured efficacy of SSRI medications. Meta-analysis demonstrated no significant association between recruitment start date and measured efficacy of SSRI pharmacotherapy (interaction= -0.11 [95% CI: -0.24 to 0.01]; p=.06; loge[week+1]=237 [95%CI: -19.7 to 494], p=.06). CY-BOCS = Children’s Yale-Brown Obsessive Compulsive Disorder Scale. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions

Figure S3 Selective serotonin reuptake inhibitor (SSRI) response curve in children as compared to adults with obsessive-compulsive disorder (OCD). Note: Meta-analysis demonstrated no significant difference between SSRI response in children and adults with OCD. The best fit model indicated a significant effect of time (log [week+1] = 1.33 [95% CI: 1.13 to 1.54]; p<.0001), and children demonstrated a lesser response compared to adults, but not to a statistically significant degree (interaction=-0.41[95% CI: -0.93 to 0.1]; p=.11). Y-BOCS = Yale-Brown Obsessive Compulsive Disorder Scale. Journal of the American Academy of Child & Adolescent Psychiatry 2016 55, 851-859.e2DOI: (10.1016/j.jaac.2016.07.768) Copyright © 2016 American Academy of Child and Adolescent Psychiatry Terms and Conditions